This invention relates to pharmaceutical combinations of amlodipine and pharmaceutically acceptable acid addition salts thereof and atorvastatin and pharmaceutically acceptable salts thereof, kits containing such combinations and methods of using such combinations to treat subjects suffering from angina pectoris, atherosclerosis, combined hypertension and hyperlipidemia and to treat subjects presenting with symptoms of cardiac risk, including humans. This invention also relates to additive and synergistic combinations of amlodipine and atorvastatin whereby those additive and synergistic combinations are useful in treating subjects suffering from angina pectoris, atherosclerosis, combined hypertension and hyperlipidemia and those subjects presenting with symptoms or signs of cardiac risk, including humans.
The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate is an early and rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by the enzyme HMG-CoA reductase. Statins inhibit HMG-CoA reductase from catalyzing this conversion. As such, statins are collectively potent lipid lowering agents.
Atorvastatin calcium, disclosed in U.S. Pat. No. 5,273,995, which is incorporated herein by reference, is currently sold as Lipitorxc2x0 and has the formula 
Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA. As such, atorvastatin calcium is apotent lipid lowering compound. The free carboxylic acid form of atorvastatin exists predominantly as the lactone of the formula 
and is disclosed in U.S. Pat. No. 4,681,893, which is incorporated herein by reference.
Amlodipine and related dihydropyridine compounds are disclosed in U.S. Pat. No. 4,572,909, which is incorporated herein by reference, as potent ant-ischemic and antihypertensive agents. U.S. Pat. No. 4,879,303, which is incorporated herein by reference, discloses amlodipine benzenesulfonate salt (also termed amlodipine besylate). Amlodipine and amlodipine besylate are potent and long lasting calcium channel blockers. As such, amlodipine, amlodipine besylate and other pharmaceutically acceptable acid addition salts of amlodipine have utility as antihypertensive agents and as antiischemic agents. Amlodipine and its pharmaceutically acceptable acid addition salts are also disclosed in U.S. Pat. No. 5,155,120 as having utility in the treatment of congestive heart failure. Amlodipine besylate is currently sold as Norvasce(copyright). Amlodipine has the formula 
Atherosclerosis is a condition characterized by irregularly distributed lipid deposits in the intima of arteries, including coronary, carotid and peripheral arteries. Atherosclerotic coronary heart disease (hereinafter termed xe2x80x9cCHDxe2x80x9d) accounts for 53% of all deaths attributable to a cardiovascular event. CHD accounts for nearly one-half (about $50-60 billion) of the total U.S. cardiovascular healthcare expenditures and about 6% of the overall national medical bill each year. Despite attempts to modify secondary risk factors such as, inter alia, smoking, obesity and lack of exercise, and treatment of dyslipidemia with dietary modification and drug therapy, CHD remains the most common cause of death in the United States.
High levels of blood cholesterol and blood lipids are conditions involved in the onset of atherosclerosis. It is well known that inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) are effective in lowering the level of blood plasma cholesterol, especially low density lipoprotein cholesterol (LDL-C), in man (Brown and Goldstein, New England Journal of Medicine, 1981, 305, No. 9, 515-517). It has now been established that lowering LDL-C levels affords protection from coronary heart disease (see, e.g., The Scandinavian Simvastatin Survival Study Group: Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S), Lancet, 1994, 344, 1383-89; and Shepherd, J. et al., Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia, New England Journal of Medicine, 1995, 333,1301-07).
Angina pectoris is a severe constricting pain in the chest, often radiating from the precordium to the left shoulder and down the left arm. Often angina pectoris is due to ischemia of the heart and is usually caused by coronary disease.
Currently the treatment of symptomatic angina pectoris varies significantly from country to country. In the U.S., patients who present with symptomatic, stable angina pectoris are frequently treated with surgical procedures or PTCA. Patients who undergo PTCA or other surgical procedures designed to treat angina pectoris frequently experience complications such as restenosis. This restenosis may be manifested either as a short term proliferative response to angioplasty-induced trauma or as long term progression of the atherosclerotic process in both graft vessels and angioplastied segments.
The symptomatic management of angina pectoris involves the use of a number of drugs, frequently as a combination of two or more of the following classes: beta blockers, nitrates and calcium channel blockers. Most, if not all, of these patients require therapy with a lipid lowering agent as well. The National Cholesterol Education
Program (NCEP) recognizes patients with existing coronary artery disease as a special class requiring aggressive management of raised LDL-C.
Amlodipine helps to prevent myocardial ischemia in patients with exertional angina pectoris by reducing Total Peripheral Resistance, or afterload, which reduces the rate pressure product and thus myocardial oxygen demand at any particular level of exercise. In patients with vasospastic angina pectoris, amlodipine has been demonstrated to block constriction and thus restore myocardial oxygen supply. Further, amlodipine has been shown to increase myocardial oxygen supply by dilating the coronary arteries.
Hypertension frequently coexists with hyperlipidemia and both are considered to be major risk factors for developing cardiac disease ultimately resulting in adverse cardiac events. This clustering of risk factors is potentially due to a common mechanism. Further, patient compliance with the management of hypertension is generally better than patient compliance with hyperlipidemia. It would therefore be advantageous for patients to have a single therapy which treats both of these conditions.
Coronary heart disease is a multifactorial disease in which the incidence and severity are affected by the lipid profile, the presence of diabetes and the sex of the subject. Incidence is also affected by smoking and left ventricular hypertrophy which is secondary to hypertension. To meaningfully reduce the risk of coronary heart disease, it is important to manage the entire risk spectrum. For example, hypertension intervention trials have failed to demonstrate full normalization in cardiovascular mortality due to coronary heart disease. Treatment with cholesterol synthesis inhibitors in patients with and without coronary artery disease reduces the risk of cardiovascular morbidity and mortality.
The Framingham Heart Study, an ongoing prospective study of adult men and women, has shown that certain risk factors can be used to predict the development of coronary heart disease. (see Wilson et al., Am. J. Cardiol. 1987, 59(14):91G-94G). These factors include age, gender, total cholesterol level, high density lipoprotein (HDL) level, systolic blood pressure, cigarette smoking, glucose intolerance and cardiac enlargement (left ventricular hypertrophy on electrocardiogram, echocardiogram or enlarged heart on chest X-ray). Calculators and computers can easily be programmed using a multivariate logistic function that allows calculation of the conditional probability of cardiovascular events. These determinations, based on experience with 5,209 men and women participating in the Framingham study, estimate coronary artery disease risk over variable periods of follow-up. Modeled incidence rates range from less than 1% to greater than 80% over an arbitrarily selected six year interval. However, these rates are typically less than 10% and rarely exceed 45% in men and 25% in women.
Kramsch et al., Journal of Human Hypertension (1995) (Suppl. 1), 53-59 disclose the use of calcium channel blockers, including amlodipine, to treat atherosclerosis. That reference further suggests that atherosclerosis can be treated with a combination of amlodipine and a lipid lowering agent. Human trials have shown that calcium channel blockers have beneficial effects in the treatment of early atherosclerotic lesions. (see, e.g., Lichtlen, P. R. et al., Retardation of angiographic progression o coronary artery disease by nifedipine, Lancet, 1990, 335, 1109-13; and Waters, D. et al., A controlled clinical trial to assess the effect of a calcium channel blocker on the progression of coronary atherosclerosis, Circulation, 1990, 82, 1940-53.) U.S. Pat. No. 4,681,893 discloses that certain statins, including atorvastatin, are hypolipidemic agents and as such are useful in treating atherosclerosis. Jukema et al., Circulation, 1995 (Suppl. 1), 1-197, disclose that there is evidence that calcium channel blockers act synergistically in combination with lipid lowering agents (e.g., HMG-CoA reductase inhibitors), specifically pravastatin. Orekhov et al., Cardiovascular Drugs and Therapy, 1997, 11, 350 disclose the use of amlodipine in combination with lovastatin for the treatment of atherosclerosis.
This invention is directed to a pharmaceutical composition, hereinafter termed xe2x80x9cComposition Axe2x80x9d, comprising:
a. an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof;
b. an amount of atorvastatin or a pharmaceutically acceptable salt thereof; and
c. a pharmaceutically acceptable carrier or diluent.
This invention is particularly directed to a pharmaceutical composition, hereinafter termed xe2x80x9cComposition AAxe2x80x9d, of Composition A comprising amlodipine besylate.
This invention is more particularly directed to a pharmaceutical composition, hereinafter termed xe2x80x9cComposition ABxe2x80x9d, of Composition A comprising the hemicalcium salt of atorvastatin.
This invention is also directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition Bxe2x80x9d, for use with a second pharmaceutical composition for achieving a antihypertensive effect and a hypolipidemic effect in a mammal suffering from hypertension and hyperlipidemia, which effects are greater than the sum of the antihypertensive and hypolipidemic effects achieved by administering said first and second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
This invention is particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition BAxe2x80x9d, of Composition B wherein said second pharmaceutical composition comprises amlodipine besylate.
This invention is more particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition BBxe2x80x9d, of Composition BA comprising the hemicalcium salt of atorvastatin.
This invention is also directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition Cxe2x80x9d, for use with a second pharmaceutical composition for achieving a antihypertensive effect and a hypolipidemic effect in a mammal suffering from hypertension and hyperlipidemia, which effects are greater than the sum of the antihypertensive and hypolipidemic effects achieved by administering said first and second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent.
This invention is particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition CAxe2x80x9d, of Composition C comprising amlodipine besylate.
This invention is more particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition CBxe2x80x9d, of Composition CA wherein said second pharmaceutical composition comprises the hemicalcium salt of atorvastatin.
This invention is also directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition Dxe2x80x9d, for use with a second pharmaceutical composition for achieving a antihypertensive effect and a hypolipidemic effect in a mammal suffering from hypertension and hyperlipidemia, which effects are greater than the antihypertensive and hypolipidemic effects achieved by administering said first or second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent.
This invention is particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition DAxe2x80x9d, of Composition D comprising amlodipine besylate.
This invention is more particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition DBxe2x80x9d, of Composition DA wherein said second pharmaceutical composition comprises the hemicalcium salt of atorvastatin.
This invention is also directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition Exe2x80x9d, for use with a second pharmaceutical composition for achieving a antihypertensive effect and a hypolipidemic effect in a mammal suffering from hypertension and hyperlipidemia, which effects are greater than the antihypertensive and hypolipidemic effects achieved by administering said first or second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
This invention is particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition EAxe2x80x9d, of Composition E wherein said second pharmaceutical composition comprises amlodipine besylate.
This invention is more particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition EBxe2x80x9d of Composition EA comprising the hemicalcium salt of atorvastatin.
This invention is also directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition Fxe2x80x9d, for use with a second pharmaceutical composition for achieving an antianginal effect in a mammal suffering from angina pectoris, which effect is greater than the sum of the antiangina effects achieved by administering said first and second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent.
This invention is particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition FAxe2x80x9d, of Composition F comprising amlodipine besylate.
This invention is more particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition FBxe2x80x9d, of Composition FA wherein said second pharmaceutical composition comprises the hemicalcium salt of atorvastatin.
This invention is also directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition Gxe2x80x9d, for use with a second pharmaceutical composition for achieving an antianginal effect in a mammal suffering from angina pectoris, which effect is greater than the sum of the antiangina effects achieved by administering said first and second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
This invention is particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition Gxe2x80x9d, of Composition G wherein said second pharmaceutical composition comprises amlodipine besylate.
This invention is more particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition GBxe2x80x9d, of Composition G comprising the hemicalcium salt of atorvastatin.
This invention is also directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition Hxe2x80x9d, for use with a second pharmaceutical composition for achieving an antianginal effect in a mammal suffering from angina pectoris, which effect is greater than the antianginal effects achieved by administering said first or second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent. acceptable carrier or diluent.
This invention is particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition HAxe2x80x9d, of Composition H comprising amlodipine besylate.
This invention is more particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition HBxe2x80x9d, of Composition HA wherein said second pharmaceutical composition comprises the hemicalcium salt of atorvastatin.
This invention is also directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition Jxe2x80x9d, for use with a second pharmaceutical composition for achieving an antianginal effect in a mammal suffering from angina pectoris, which effect is greater than the antianginal effects achieved by administering said first or second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
This invention is particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition JAxe2x80x9d, of Composition J wherein said second pharmaceutical composition comprises amlodipine besylate.
This invention is more particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition JBxe2x80x9d, of Composition JA comprising the hemicalcium salt of atorvastatin.
This invention is also directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition Kxe2x80x9d, for use with a second pharmaceutical composition for achieving an antiatherosclerotic effect in a mammal, which effect is greater than the sum of the antiatherosclerotc effects achieved by administering said first and second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
This invention is particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition KAxe2x80x9d, of Composition K wherein said second pharmaceutical composition comprises amlodipine besylate.
This invention is more particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition KBxe2x80x9d, of Composition KA comprising the hemicalcium salt of atorvastatin.
This invention is still more particularly directed to a composition, hereinafter termed xe2x80x9cComposition KCxe2x80x9d, of Composition KB wherein said antiatherosclerotic effect is manifested by a slowing of the progression of atherosclerotic plaques.
This invention is still more particularly directed to a composition of Composition KC wherein said progression of atherosclerotic plaques is slowed in coronary arteries.
This invention is also particularly directed to a composition of Composition KB wherein said progression of atherosclerotic plaques is slowed in carotid arteries.
This invention is also particularly directed to a composition of Composition KB wherein said progression of atherosclerotic plaques is slowed in the peripheral arterial system.
This invention is more particularly directed to a composition, hereinafter termed xe2x80x9cComposition KDxe2x80x9d, of Composition KB wherein said antiatherosclerotic effect is manifested by a regression of atherosclerotic plaques.
This invention is still more particularly directed to a composition of Composition KD wherein said regression of atherosclerotic plaques occurs in coronary arteries.
This invention is also particularly directed to a composition of Composition KD wherein said regression of atherosclerotic plaques occurs in carotid arteries.
This invention is also particularly directed to a composition of Composition KD wherein said regression of atherosclerotic plaques occurs in the peripheral arterial system.
This invention is also directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition Lxe2x80x9d, for use with a second pharmaceutical composition for achieving an antiatherosclerotic effect in a mammal, which effect is greater than the sum of the antiatherosclerotic effects achieved by administering said first and second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent.
This invention is particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition LAxe2x80x9d, of Composition L comprising amlodipine besylate.
This invention is more particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition LBxe2x80x9d, of Composition LA wherein said second pharmaceutical composition comprises the hemicalcium salt of atorvastatin.
This invention is still more particularly directed to a composition, hereinafter termed xe2x80x9cLCxe2x80x9d, of Composition LB wherein said antiatherosclerotic effect is manifested by a slowing of the progression of atherosclerotic plaques.
This invention is still more particularly directed to a composition of Composition LC wherein said progression of atherosclerotic plaques is slowed in coronary arteries.
This invention is also particularly directed to a composition of Composition LC wherein said progression of atherosclerotic plaques is slowed in carotid arteries.
This invention is also particularly directed to a composition of Composition LC wherein said progression of atherosclerotic plaques is slowed in the peripheral arterial system.
This invention is more particularly directed to a composition, hereinafter termed xe2x80x9cComposition LDxe2x80x9d, of Composition LB wherein said antiatherosclerotic effect is manifested by a regression of atherosclerotic plaques.
This invention is still more particularly directed to a composition of Composition LD wherein said regression of atherosclerotic plaques occurs in coronary arteries.
This invention is also particularly directed to a composition of Composition LD wherein said regression of atherosclerotic plaques occurs in carotid arteries.
This invention is also particularly directed to a composition of Composition LD wherein said regression of atherosclerotic plaques occurs in the peripheral arterial system.
This invention is also directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition Mxe2x80x9d, for use with a second pharmaceutical composition for achieving an antiatherosclerotic effect in a mammal, which effect is greater than the antiatherosclerotic effects achieved by administering said first or second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent.
This invention is particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition MAxe2x80x9d, of Composition M comprising amlodipine besylate.
This invention is more particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition MBxe2x80x9d, of Composition MA wherein said second pharmaceutical composition comprises the hemicalcium salt of atorvastatin.
This invention is still more particularly directed to a composition, hereinafter termed xe2x80x9cComposition MCxe2x80x9d, of Composition MB wherein said antiatherosclerotic effect is manifested by a slowing of the progression of atherosclerotic plaques.
This invention is still more particularly directed to a composition of Composition MC wherein said progression of atherosclerotic plaques is slowed in coronary arteries.
This invention is also particularly directed to a composition of Composition MC wherein said progression of atherosclerotic plaques is slowed in carotid arteries.
This invention is also particularly directed to a composition of Composition MC wherein said progression of atherosclerotic plaques is slowed in the peripheral arterial system.
This invention is more particularly directed to a composition, hereinafter termed xe2x80x9cComposition MDxe2x80x9d, of Composition MB wherein said antiatherosclerotic effect is manifested by a regression of atherosclerotic plaques.
This invention is still more particularly directed to a composition of Composition MD wherein said regression of atherosclerotic plaques occurs in coronary arteries.
This invention is also particularly directed to a composition of Composition MD wherein said regression of atherosclerotic plaques occurs in carotid arteries.
This invention is also particularly directed to a composition of Composition MD wherein said regression of atherosclerotic plaques occurs in the peripheral arterial system.
This invention is also directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition Nxe2x80x9d, for use with a second pharmaceutical composition for achieving an antiatherosclerotic effect in a mammal, which effect is greater than the antiatherosclerotic effects achieved by administering said first or second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
This invention is particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition NAxe2x80x9d, of Composition N wherein said second pharmaceutical composition comprises amlodipine besylate.
This invention is more particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition NBxe2x80x9d, of Composition NA comprising the hemicalcium salt of atorvastatin.
This invention is still more particularly directed to a composition, hereinafter termed xe2x80x9cComposition NCxe2x80x9d, of Composition NB wherein said antiatherosclerotic effect is manifested by a slowing of the progression of atherosclerotic plaques.
This invention is still more particularly directed to a composition of Composition NC wherein said progression of atherosclerotic plaques is slowed in coronary arteries.
This invention is also particularly directed to a composition of Composition NC wherein said progression of atherosclerotic plaques is slowed in carotid arteries.
This invention is also particularly directed to a composition of Composition NC wherein said progression of atherosclerotic plaques is slowed in the peripheral arterial system.
This invention is more particularly directed to a composition, hereinafter termed xe2x80x9cComposition NDxe2x80x9d, of Composition NB wherein said antiatherosclerotic effect is manifested by a regression of atherosclerotic plaques.
This invention is still more particularly directed to a composition of Composition ND wherein said regression of atherosclerotic plaques occurs in coronary arteries.
This invention is also particularly directed to a composition of Composition ND wherein said regression of atherosclerotic plaques occurs in carotid arteries.
This invention is also particularly directed to a composition of Composition ND wherein said regression of atherosclerotic plaques occurs in the peripheral arterial system.
This invention is also directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition Pxe2x80x9d, for use with a second pharmaceutical composition for managing cardiac risk in a mammal at risk of suffering an adverse cardiac event, which effect is greater than the sum of the cardiac risk management effects achieved by administering said first and second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable add addition salt thereof and a pharmaceutically acceptable carrier or diluent.
This invention is particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition PAxe2x80x9d, of Composition P comprising amlodipine besylate.
This invention is more particularly directed to a first pharmaceutical composition of Composition PA wherein said second pharmaceutical composition comprises the hemicalcium salt of atorvastatin.
This invention is also directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition Qxe2x80x9d, for use with a second pharmaceutical composition for managing cardiac risk in a mammal at risk of suffering an adverse cardiac event, which effect is greater than the sum of the cardiac risk management effects achieved by administering said first and second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
This invention is particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition QAxe2x80x9d, of Composition Q wherein said second pharmaceutical composition comprises amlodipine besylate.
This invention is more particularly directed to a first pharmaceutical composition of Composition QA comprising the hemicalcium salt of atorvastatin.
This invention is also directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition Rxe2x80x9d, for use with a second pharmaceutical composition for managing cardiac risk in a mammal at risk of suffering an adverse cardiac event, which effect is greater than the cardiac risk management effects achieved by administering said first or second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent.
This invention is particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition RADxe2x80x9d, of Composition R comprising amlodipine besylate.
This invention is more particularly directed to a first pharmaceutical composition of Composition RA wherein said second pharmaceutical composition comprises the hemicalcium salt of atorvastatin.
This invention is also directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition Sxe2x80x9d, for use with a second pharmaceutical composition for managing cardiac risk in a mammal at risk of suffering an adverse cardiac event, which effect is greater than the cardiac risk management effects achieved by administering said first or second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
This invention is particularly directed to a first pharmaceutical composition, hereinafter termed xe2x80x9cComposition SAxe2x80x9d, of Composition S wherein said second pharmaceutical composition comprises amlodipine besylate.
This invention is more particularly directed to a first pharmaceutical composition of Composition S comprising the hemicalcium salt of atorvastatin.
This invention is also directed to a kit, hereinafter termed xe2x80x9cKit Axe2x80x9d, for achieving a therapeutic effect in a mammal comprising:
a. an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent in a first unit dosage form;
b. an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and
c. container means for containing said first and second dosage forms.
This invention is particularly directed to a kit, hereinafter termed xe2x80x9cKit Mxe2x80x9d, of Kit A comprising amlodipine besylate.
This invention is more particularly directed to a kit, hereinafter termed xe2x80x9cKit ABxe2x80x9d, of Kit AA comprising the hemicalcium salt of atorvastatin.
This invention is still more particularly directed to a kit, hereinafter termed xe2x80x9cKit ACxe2x80x9d, of Kit AB wherein said therapeutic effect is treatment of hypertension and hyperlipidemia.
This invention is still more particularly directed to a kit, hereinafter termed xe2x80x9cKit ADxe2x80x9d, of Kit AB wherein said therapeutic effect is treatment of angina pectoris.
This invention is also particularly directed to a kit, hereinafter termed xe2x80x9cKit AExe2x80x9dof Kit AB wherein said therapeutic effect is management of cardiac risk.
This invention is also particularly directed to a kit, hereinafter termed xe2x80x9cKit AFxe2x80x9d, of Kit AB wherein said therapeutic effect is treatment of atherosclerosis.
This invention is still more particularly directed to a kit, hereinafter termed xe2x80x9cKit AGxe2x80x9d, of Kit AF wherein said treatment of atherosclerosis slows the progression of atherosclerotic plaques.
This invention is further directed to a kit, hereinafter termed xe2x80x9cKit AHxe2x80x9d, of Kit AG wherein said progression of atherosclerotic plaques is slowed in coronary arteries.
This invention is still further directed to a kit, hereinafter termed xe2x80x9cKit AJxe2x80x9d, of Kit AG wherein said progression of atherosclerotic plaques is slowed in carotid arteries.
This invention is still further directed to a kit, hereinafter termed xe2x80x9cKit AKxe2x80x9d, of Kit AG wherein said progression of atherosclerotic plaques is slowed in the peripheral arterial system.
This invention is still further directed to a kit, hereinafter termed xe2x80x9cKit ALxe2x80x9d, of Kit AF wherein said treatment of atherosclerosis causes the regression of atherosclerotic plaques.
This invention is still further directed to a kit of Kit AL wherein said regression of atherosclerotic plaques occurs in coronary arteries.
This invention is still further directed to a kit of Kit AL wherein said regression of atherosclerotic plaques occurs in carotid arteries.
This invention is still further directed to a kit of Kit AL wherein said regression of atherosclerotic plaques occurs in the peripheral arterial system.
This invention is also directed to a method, hereinafter termed xe2x80x9cMethod Axe2x80x9d, for treating a mammal in need of therapeutic treatment comprising administering to said mammal
(a) an amount of a first compound, said first compound being amlodipine or a pharmaceutically acceptable acid addition salt thereof; and
(b) an amount of a second compound, said second compound being atorvastatin or a pharmaceutically acceptable salt thereof;
wherein said first compound and said second compound are each optionally and independently administered together with a pharmaceutically acceptable carrier or diluent.
This invention is particularly directed to a method, hereinafter Method B, of Method A comprising amlodipine besylate.
This invention is more particularly directed to a method, hereinafter termed xe2x80x9cMethod Cxe2x80x9d, of Method B comprising the hemicalcium salt of atorvastatin.
This invention is still more particularly directed to a method, hereinafter termed xe2x80x9cMethod Dxe2x80x9d, of Method A wherein said first compound and said second compound are administered simultaneously.
This invention is still more particularly directed to a method, hereinafter termed xe2x80x9cMethod Exe2x80x9d, of Method A wherein said first compound and said second compound are administered sequentially in either order.
This invention is also particularly directed to a method, hereinafter termed xe2x80x9cMethod Fxe2x80x9d, of Method C wherein said first compound and said second compound are administered simultaneously.
This invention is further directed to a method, hereinafter termed xe2x80x9cMethod Gxe2x80x9d, of Method C wherein said first compound and said second compound are administered sequentially in either order.
This invention is still further directed to a method of Method A wherein said therapeutic treatment comprises antihypertensive treatment and antihyperlipidemic treatment.
This invention is still further directed to a method of Method F wherein said therapeutic treatment comprises antihypertensive treatment and antihyperlipidemic treatment.
This invention is still further directed to a method of Method G wherein said therapeutic treatment comprises antihypertensive treatment and antihyperlipidemic treatment.
This invention is further directed to a method of Method A wherein said therapeutic treatment comprises antianginal treatment.
This invention is further directed to a method of Method F wherein said therapeutic treatment comprises antianginal treatment.
This invention is further directed to a method of Method G wherein said therapeutic treatment comprises antianginal treatment.
This invention is further directed to a method of Method A wherein said therapeutic treatment comprises cardiac risk management.
This invention is further directed to a method of Method F wherein said therapeutic treatment comprises cardiac risk management.
This invention is further directed to a method of Method G wherein said therapeutic treatment comprises cardiac risk management.
This invention is further directed to a method of Method A wherein said therapeutic treatment comprises antiatherosclerotic treatment.
This invention is further directed to a method of Method F wherein said therapeutic treatment comprises antiatherosclerotic treatment.
This invention is further directed to a method of Method G wherein said therapeutic treatment comprises antiatherosclerotic treatment.
Amlodipine is a racemic compound due to the symmetry at position 4 of the dihydropyridine ring. The R and S enantiomers may be prepared as described by Arrowsmith et al., J. Med. Chem., 1986, 29, 1696. The calcium channel blocking activity of amlodipine is substantially confined to the S(xe2x88x92) isomer and to the racemic mixture containing the R(+) and S(xe2x88x92) forms. (see International Patent Application Number PCT/EP94/02697). The R(+) isomer has little or no calcium channel blocking activity. However, the R(+) isomer is a potent inhibitor of smooth muscle cell migration. Thus, the R(+) isomer is useful in the treatment or prevention of atherosclerosis. (see International Patent Application Number PCT/EP95/00847). Based on the above, a skilled person could choose the R(+) isomer, the S(xe2x88x92) isomer or the racemic mixture of the R(+) isomer and the S(xe2x88x92) isomer for use in the combination of this invention.
Where used herein, the term xe2x80x9ccardiac riskxe2x80x9d, means the likelihood that a subject will suffer a future adverse cardiac event such as, e.g., myocardial infarction, cardiac arrest, cardiac failure, cardiac ischaemia. Cardiac risk is calculated using the Framingham Risk Equation as set forth above. The term xe2x80x9ccardiac risk managementxe2x80x9d means that the risk of future adverse cardiac events is substantially reduced.